Gastroesophageal reflux disease (GERD) is a chronic, relapsing condition with associated morbidity and an adverse impact on quality of life. The disease is common, with an estimated lifetime prevalence of 25 to 35 percent in the U.S. population. Psychological well-being questionnaires indicate that patients with GERD can have a poor quality of life. Indeed, the combination of symptoms, dietary restrictions, and functional limitations take their toll on an individual's sense of well-being.
In addition to the poor quality of life experienced by GERD sufferers, annual health care costs related to this disease are high. Individuals who suffer from GERD are prone to complications such as severe esophagitis, recurrent esophageal strictures, severe pulmonary symptoms, and Barrett's esophagus, which carries with it an increased risk for the development of adenocarcinoma of the esophagus.
Antacids remain the drugs of choice for quick relief of symptoms associated with GERD. These agents act primarily by rapidly increasing the pH of the gastric refluxate. Although antacids are effective in relieving symptoms, they cannot be used as sole agents for achieving esophageal healing because of the high dosage requirements and consequent lack of patient compliance.
Over-the-Counter H2-Receptor Blockers may also be prescribed for the treatment and prevention of GERD. These agents are indicated for the prevention and relief of heartburn, acid indigestion and sour stomach. They do not act as rapidly as antacids, but they provide longer relief of symptoms. Unfortunately, standard dosages of these agents do not completely inhibit acid secretion, and so do not typically promote esophageal healing.
Clearly, there is a need in the art for a safe and effective GERD treatment that will reduce and/or eliminate the causes and/or symptoms of GERD. The ideal treatment would also promote healing of damaged esophageal tissues, thereby reducing health cost associated with the disease. Fortunately, the current invention addresses these and other needs. The invention is based, at least in part, on the surprising discovery that glucocorticoid receptor antagonists are effective agents for the treatment of GERD.
Corticosteroids are steroid hormones released by the adrenal glands. The most significant human adrenal corticosteroids are cortisol, corticosterone and aldosterone. Corticosteroids produce cellular effects following binding to receptors located in the cytoplasm of the cell. Two general classes of corticosteroid receptors are now recognized, the mineralocorticoid receptors (also termed type I, or MR) and the glucocorticoid receptors (also termed type II, or GR).
Mineralocorticoid receptors (MRs) bind cortisol with ten-fold higher affinity than glucocorticoid receptors (GRs) bind glucocorticoids. Thus, the activation of the two classes of receptors may differ depending on the corticosteroid (cortisol) concentration. Blood levels of the glucocorticoid cortisol vary over a wide range during the day. In general, normal cortisol concentrations in the blood range from about 0.5 nM to about 50 nM; however, in response to stress, cortisol concentration may exceed 100 nM.
Glucocorticoid blockers are agents that block or reduce the effects of glucocorticoids. Such interference with glucocorticoid action may, for example, be due to interference with binding of glucocorticoid agonists to glucocorticoid receptors (GR), or to interference with the action of agonist-bound GR at the cell nucleus, or to interference with expression or processing of gene products induced by the action of agonist-bound GR at the nucleus. Glucocorticoid receptor antagonists (GR antagonists) are compounds which inhibit the effect of the native ligand or of glucocorticoid agonists on GR. One mode of action of GR antagonists is to inhibit the binding of GR ligands to GR. A discussion of glucocorticoid antagonists may be found in Agarwal et al. “Glucocorticoid antagonists”, FEBS Lett., 217:221-226 (1987). An example of a GR antagonist is mifepristone, (11β,17β) 11[4(dimethylamino)phenyl]-17hydroxy-17(1 propynyl)estra-4,9dien-3one, also known as RU-486 or RU-38486. See U.S. Pat. No. 4,368,085. Mifepristone binds specifically to GR with an affinity about 18 times that of the affinity of cortisol for GR. GR antagonists may be steroids, such as mifepristone, or non-steroids.
The present inventors have determined for the first time that glucocorticoid receptor antagonists are effective agents for the treatment of gastroesophageal reflux disease. Thus, the present invention fulfills the need for an effective method for the treatment of gastroesophageal reflux disease by providing methods of administering glucocorticoid receptor antagonists to a subject.